Whole-Body Pattern of Muscle Degeneration and Progression in Sarcoglycanopathies

Laura Costa-Comellas; Mauro Monforte; Angel Sanchez-Montañez; Penélope Romero-Duque; Elena Pegoraro; Jordi Díaz-Manera; Dmitry Vlodavets; Lorenzo Maggi; Marco Moscatelli; Adele D'Amico; Montse Olivé; Jorge Alonso-Pérez; Giacomo Comi; José Miguel Escudero-Fernández; Gabriela S Urcuyo; Anna Pichiecchio; Angela Berardinelli; Kristl G Claeys; Claudio Bruno; Chiara Panicucci; Sara Bortolani; Eleonora Torchia; Enzo Ricci; Soledad Monges; Jorge A Bevilacqua; Jorge Diaz-Jara; Maggie C Walter; Simone Thiele; Nicoline Løkken; John Vissing; Susana Quijano-Roy; Robert Y Carlier; Nicol C Voermans; Chiara Marini-Bettolo; Michela Guglieri; Volker Straub; Lea Leonardis; Francina Munell; David Gómez-Andrés; Giorgio Tasca

doi:10.1002/acn3.70303

Whole-Body Pattern of Muscle Degeneration and Progression in Sarcoglycanopathies

Laura Costa-Comellas, Mauro Monforte, Angel Sanchez-Montañez, Penélope Romero-Duque, Elena Pegoraro, Jordi Díaz-Manera, Dmitry Vlodavets, Lorenzo Maggi, Marco Moscatelli, Adele D'Amico, Montse Olivé, Jorge Alonso-Pérez, Giacomo Comi, José Miguel Escudero-Fernández, Gabriela S Urcuyo, Anna Pichiecchio, Angela Berardinelli, Kristl G Claeys, Claudio Bruno, Chiara PanicucciSara Bortolani, Eleonora Torchia, Enzo Ricci, Soledad Monges, Jorge A Bevilacqua, Jorge Diaz-Jara, Maggie C Walter, Simone Thiele, Nicoline Løkken, John Vissing, Susana Quijano-Roy, Robert Y Carlier, Nicol C Voermans, Chiara Marini-Bettolo, Michela Guglieri, Volker Straub, Lea Leonardis, Francina Munell, David Gómez-Andrés^*, Giorgio Tasca^*

^*Corresponding author af dette arbejde

Afdeling for Hjerne- og Nervesygdomme NEU

Abstract

OBJECTIVE: To characterize whole-body intramuscular fat distribution pattern in patients with sarcoglycanopathies and explore correlations with disease severity, duration and age at onset.

METHODS: Retrospective, cross-sectional, multicentric study enrolling patients with variants in one of the four sarcoglycan genes who underwent whole-body muscle MRI. Intramuscular fatty replacement was evaluated on T1-weighted images and represented by heatmaps. Dimensionality reduction and linear spline models examined relationships between patterns of intramuscular fat replacement and clinical findings.

RESULTS: MRI scans from 64 patients (age range 4-67 years) covering 4160 muscles were analyzed. Disease severity ranged from asymptomatic (9%) to non-ambulant (39%) patients. Sarcoglycanopathies showed consistent, selective patterns of muscle involvement across genotypes. Latissimus dorsi and subscapularis were the earliest affected muscles in the upper body, whereas head, neck and forearm muscles remained largely preserved. Distinct gradients characterized the topography of degeneration both within individual muscles and along body and limb axes. Disease severity correlated with MRI changes in both upper and lower body muscles, and with one of the dimensions identified by the multi-correspondence analysis. Patients with onset in the first decade showed a steeper cross-sectional association between disease duration and MRI abnormalities, while later-onset patients displayed a more gradual, linear relationship.

INTERPRETATION: Sarcoglycanopathies display selective muscle vulnerability with characteristic gradients of fat replacement. Scapular girdle muscles are affected early in the disease course. Intramuscular fat correlates with functional impairment and disease duration, supporting its use as a surrogate endpoint in clinical trials. Age at onset emerges as a critical prognostic factor.

Originalsprog	Engelsk
Tidsskrift	Annals of Clinical and Translational Neurology
ISSN	2328-9503
DOI	https://doi.org/10.1002/acn3.70303
Status	E-pub ahead of print - 31 dec. 2025

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10.1002/acn3.70303Licens: CC BY

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Costa-Comellas, L., Monforte, M., Sanchez-Montañez, A., Romero-Duque, P., Pegoraro, E., Díaz-Manera, J., Vlodavets, D., Maggi, L., Moscatelli, M., D'Amico, A., Olivé, M., Alonso-Pérez, J., Comi, G., Escudero-Fernández, J. M., Urcuyo, G. S., Pichiecchio, A., Berardinelli, A., Claeys, K. G., Bruno, C., ... Tasca, G. (2025). Whole-Body Pattern of Muscle Degeneration and Progression in Sarcoglycanopathies. Annals of Clinical and Translational Neurology. Advance online publication. https://doi.org/10.1002/acn3.70303

Costa-Comellas, L, Monforte, M, Sanchez-Montañez, A, Romero-Duque, P, Pegoraro, E, Díaz-Manera, J, Vlodavets, D, Maggi, L, Moscatelli, M, D'Amico, A, Olivé, M, Alonso-Pérez, J, Comi, G, Escudero-Fernández, JM, Urcuyo, GS, Pichiecchio, A, Berardinelli, A, Claeys, KG, Bruno, C, Panicucci, C, Bortolani, S, Torchia, E, Ricci, E, Monges, S, Bevilacqua, JA, Diaz-Jara, J, Walter, MC, Thiele, S, Løkken, N , Vissing, J, Quijano-Roy, S, Carlier, RY, Voermans, NC, Marini-Bettolo, C, Guglieri, M, Straub, V, Leonardis, L, Munell, F, Gómez-Andrés, D & Tasca, G 2025, 'Whole-Body Pattern of Muscle Degeneration and Progression in Sarcoglycanopathies', Annals of Clinical and Translational Neurology. https://doi.org/10.1002/acn3.70303

@article{dcde0778bac34abebaee6ccccfe1210e,

title = "Whole-Body Pattern of Muscle Degeneration and Progression in Sarcoglycanopathies",

abstract = "OBJECTIVE: To characterize whole-body intramuscular fat distribution pattern in patients with sarcoglycanopathies and explore correlations with disease severity, duration and age at onset.METHODS: Retrospective, cross-sectional, multicentric study enrolling patients with variants in one of the four sarcoglycan genes who underwent whole-body muscle MRI. Intramuscular fatty replacement was evaluated on T1-weighted images and represented by heatmaps. Dimensionality reduction and linear spline models examined relationships between patterns of intramuscular fat replacement and clinical findings.RESULTS: MRI scans from 64 patients (age range 4-67 years) covering 4160 muscles were analyzed. Disease severity ranged from asymptomatic (9%) to non-ambulant (39%) patients. Sarcoglycanopathies showed consistent, selective patterns of muscle involvement across genotypes. Latissimus dorsi and subscapularis were the earliest affected muscles in the upper body, whereas head, neck and forearm muscles remained largely preserved. Distinct gradients characterized the topography of degeneration both within individual muscles and along body and limb axes. Disease severity correlated with MRI changes in both upper and lower body muscles, and with one of the dimensions identified by the multi-correspondence analysis. Patients with onset in the first decade showed a steeper cross-sectional association between disease duration and MRI abnormalities, while later-onset patients displayed a more gradual, linear relationship.INTERPRETATION: Sarcoglycanopathies display selective muscle vulnerability with characteristic gradients of fat replacement. Scapular girdle muscles are affected early in the disease course. Intramuscular fat correlates with functional impairment and disease duration, supporting its use as a surrogate endpoint in clinical trials. Age at onset emerges as a critical prognostic factor.",

author = "Laura Costa-Comellas and Mauro Monforte and Angel Sanchez-Monta{\~n}ez and Pen{\'e}lope Romero-Duque and Elena Pegoraro and Jordi D{\'i}az-Manera and Dmitry Vlodavets and Lorenzo Maggi and Marco Moscatelli and Adele D'Amico and Montse Oliv{\'e} and Jorge Alonso-P{\'e}rez and Giacomo Comi and Escudero-Fern{\'a}ndez, {Jos{\'e} Miguel} and Urcuyo, {Gabriela S} and Anna Pichiecchio and Angela Berardinelli and Claeys, {Kristl G} and Claudio Bruno and Chiara Panicucci and Sara Bortolani and Eleonora Torchia and Enzo Ricci and Soledad Monges and Bevilacqua, {Jorge A} and Jorge Diaz-Jara and Walter, {Maggie C} and Simone Thiele and Nicoline L{\o}kken and John Vissing and Susana Quijano-Roy and Carlier, {Robert Y} and Voermans, {Nicol C} and Chiara Marini-Bettolo and Michela Guglieri and Volker Straub and Lea Leonardis and Francina Munell and David G{\'o}mez-Andr{\'e}s and Giorgio Tasca",

note = "{\textcopyright} 2025 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.",

year = "2025",

month = dec,

day = "31",

doi = "10.1002/acn3.70303",

language = "English",

journal = "Annals of Clinical and Translational Neurology",

issn = "2328-9503",

publisher = "John Wiley & Sons Inc.",

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TY - JOUR

T1 - Whole-Body Pattern of Muscle Degeneration and Progression in Sarcoglycanopathies

AU - Costa-Comellas, Laura

AU - Monforte, Mauro

AU - Sanchez-Montañez, Angel

AU - Romero-Duque, Penélope

AU - Pegoraro, Elena

AU - Díaz-Manera, Jordi

AU - Vlodavets, Dmitry

AU - Maggi, Lorenzo

AU - Moscatelli, Marco

AU - D'Amico, Adele

AU - Olivé, Montse

AU - Alonso-Pérez, Jorge

AU - Comi, Giacomo

AU - Escudero-Fernández, José Miguel

AU - Urcuyo, Gabriela S

AU - Pichiecchio, Anna

AU - Berardinelli, Angela

AU - Claeys, Kristl G

AU - Bruno, Claudio

AU - Panicucci, Chiara

AU - Bortolani, Sara

AU - Torchia, Eleonora

AU - Ricci, Enzo

AU - Monges, Soledad

AU - Bevilacqua, Jorge A

AU - Diaz-Jara, Jorge

AU - Walter, Maggie C

AU - Thiele, Simone

AU - Løkken, Nicoline

AU - Vissing, John

AU - Quijano-Roy, Susana

AU - Carlier, Robert Y

AU - Voermans, Nicol C

AU - Marini-Bettolo, Chiara

AU - Guglieri, Michela

AU - Straub, Volker

AU - Leonardis, Lea

AU - Munell, Francina

AU - Gómez-Andrés, David

AU - Tasca, Giorgio

PY - 2025/12/31

Y1 - 2025/12/31

N2 - OBJECTIVE: To characterize whole-body intramuscular fat distribution pattern in patients with sarcoglycanopathies and explore correlations with disease severity, duration and age at onset.METHODS: Retrospective, cross-sectional, multicentric study enrolling patients with variants in one of the four sarcoglycan genes who underwent whole-body muscle MRI. Intramuscular fatty replacement was evaluated on T1-weighted images and represented by heatmaps. Dimensionality reduction and linear spline models examined relationships between patterns of intramuscular fat replacement and clinical findings.RESULTS: MRI scans from 64 patients (age range 4-67 years) covering 4160 muscles were analyzed. Disease severity ranged from asymptomatic (9%) to non-ambulant (39%) patients. Sarcoglycanopathies showed consistent, selective patterns of muscle involvement across genotypes. Latissimus dorsi and subscapularis were the earliest affected muscles in the upper body, whereas head, neck and forearm muscles remained largely preserved. Distinct gradients characterized the topography of degeneration both within individual muscles and along body and limb axes. Disease severity correlated with MRI changes in both upper and lower body muscles, and with one of the dimensions identified by the multi-correspondence analysis. Patients with onset in the first decade showed a steeper cross-sectional association between disease duration and MRI abnormalities, while later-onset patients displayed a more gradual, linear relationship.INTERPRETATION: Sarcoglycanopathies display selective muscle vulnerability with characteristic gradients of fat replacement. Scapular girdle muscles are affected early in the disease course. Intramuscular fat correlates with functional impairment and disease duration, supporting its use as a surrogate endpoint in clinical trials. Age at onset emerges as a critical prognostic factor.

AB - OBJECTIVE: To characterize whole-body intramuscular fat distribution pattern in patients with sarcoglycanopathies and explore correlations with disease severity, duration and age at onset.METHODS: Retrospective, cross-sectional, multicentric study enrolling patients with variants in one of the four sarcoglycan genes who underwent whole-body muscle MRI. Intramuscular fatty replacement was evaluated on T1-weighted images and represented by heatmaps. Dimensionality reduction and linear spline models examined relationships between patterns of intramuscular fat replacement and clinical findings.RESULTS: MRI scans from 64 patients (age range 4-67 years) covering 4160 muscles were analyzed. Disease severity ranged from asymptomatic (9%) to non-ambulant (39%) patients. Sarcoglycanopathies showed consistent, selective patterns of muscle involvement across genotypes. Latissimus dorsi and subscapularis were the earliest affected muscles in the upper body, whereas head, neck and forearm muscles remained largely preserved. Distinct gradients characterized the topography of degeneration both within individual muscles and along body and limb axes. Disease severity correlated with MRI changes in both upper and lower body muscles, and with one of the dimensions identified by the multi-correspondence analysis. Patients with onset in the first decade showed a steeper cross-sectional association between disease duration and MRI abnormalities, while later-onset patients displayed a more gradual, linear relationship.INTERPRETATION: Sarcoglycanopathies display selective muscle vulnerability with characteristic gradients of fat replacement. Scapular girdle muscles are affected early in the disease course. Intramuscular fat correlates with functional impairment and disease duration, supporting its use as a surrogate endpoint in clinical trials. Age at onset emerges as a critical prognostic factor.

U2 - 10.1002/acn3.70303

DO - 10.1002/acn3.70303

M3 - Journal article

C2 - 41475892

SN - 2328-9503

JO - Annals of Clinical and Translational Neurology

JF - Annals of Clinical and Translational Neurology

ER -

Whole-Body Pattern of Muscle Degeneration and Progression in Sarcoglycanopathies

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